Role of Oxidative Stress and Inflammation in Doxorubicin-Induced Cardiotoxicity: A Brief Account

Abstract

Cardiotoxicity is the main side effect of several chemotherapeutic drugs. Doxorubicin (Doxo) is one of the most used anthracyclines in the treatment of many tumors, but the development of acute and chronic cardiotoxicity limits its clinical usefulness. Different studies focused only on the effects of long-term Doxo administration, but recent data show that cardiomyocyte damage is an early event induced by Doxo after a single administration that can be followed by progressive functional decline, leading to overt heart failure. The knowledge of molecular mechanisms involved in the early stage of Doxo-induced cardiotoxicity is of paramount importance to treating and/or preventing it. This review aims to illustrate several mechanisms thought to underlie Doxo-induced cardiotoxicity, such as oxidative and nitrosative stress, inflammation, and mitochondrial dysfunction. Moreover, here we report data from both in vitro and in vivo studies indicating new therapeutic strategies to prevent Doxo-induced cardiotoxicity.

Keywords: Doxorubicin; cardiotoxicity; inflammation; oxidative stress.

Figure 1

Interference of Semiquinone in the redox cycle. NADPH oxidase is involved in the generation of the Semiquinone form of Doxo. The Quinone form is regenerated by the presence of oxygen, forming superoxide, a highly reactive species. Indeed, superoxide interacts with nitric oxide to form the peroxynitrite anion, a potent free radical; in addition, superoxide is converted into peroxide by SOD. Hydrogen peroxide is responsible for the formation of hydroxyl radicals, leading to DNA, protein, and lipid damage. Abbreviations: SOD, Superoxide dismutase; NOs, nitric oxide synthetase.

Figure 2

Involvement of Doxo–Fe complexes in oxidative stress and lipid peroxidation. Doxo has a high affinity for iron, leading to the formation of Doxo–Fe complexes. Doxo–Fe³⁺ complexes can be reduced by several reducing systems, such as Gpx4, to form the Doxo–Fe²⁺ complex. The latter is involved in both increasing oxidative stress through interactions with O₂ and inducing lipid peroxidation through interactions with the negative charge of the membrane.

Figure 3

Involvement of Nrf2 in Doxo-induced cardiotoxicity. Nrf2 is negatively regulated by Keap-1; Keap-1 degradation induces activation and nuclear translocation of Nrf2, which thereby upregulates several antioxidant enzymes (GST, OH-1, and NQO1). The effects of Doxo on Nrf2 are controversial, as reported in panels (A–C). (A). Doxo-induced oxidative stress leads to activation of Nrf2 and its nuclear translocation to increase the levels of antioxidant enzymes. (B). Doxo can inhibit Nrf2 by interfering with p38MAPK. The phosphorylation of Nrf2 is reduced and interaction with ARE in the nucleus is hindered. (C). Doxo can induce an increase in Keap-1 levels, thereby disrupting the dissociation of the Keap-1/Nrf2 complex. In this way, nuclear translocation of Nrf2 is inhibited. Dashed lines indicate blocking of the mechanism. Abbreviations. Nrf2, Nuclear factor erythroid 2 like; Keap-1, Kelch-Like ECH associated protein 1; GST, Glutathione S-transferase; HO-1, heme oxygenase-1; NQO1, NAD(P)H quinone dehydrogenase 1; ARE, Antioxidant response elements; p38MAPK, p38 mitogen-activated protein kinase.

Figure 4

Schematic representation of different mechanisms involved in Doxo-induced cardiotoxicity. Doxorubicin is involved in increased ROS and NOS levels, which promote oxidative stress. In addition, it activates NF-kB, TLR4, and NLRP3, which are involved in enhancing levels of pro-inflammatory cytokines. Lipid peroxidation is caused by Doxo–iron complexes, and the reduction in antioxidant enzymes is related to the inactivation of Nrf2. Abbreviations: ROS, Reactive oxygen species; NOS, Reactive nitrogen species; NF-kB, Nuclear factor kappaB; TLR4, Tool-like receptor 4; NLRP3, NLR family pyrin domain containing 3; Nrf2, Nuclear factor erythroid 2 like.